A genetic shift in an escaped transmitted/founder virus guides combinatorial vaccine design against HIV-1

A productive HIV-1 infection is often established by a single transmitted/founder (T/F) virus, which then evolves into a complex mixture of variants during the lifetime of infection. An effective vaccine should have sufficient breadth to block the entry of diverse T/F involved in different infections. Although the variable V1V2 domain of HIV-1 envelope protein (Env) is found to be a good target for vaccine design based on the correlates of protection in the modestly successful RV144 trial, the breadth of immune responses has to be substantially enhanced to improve vaccine efficacy and minimize the emergence of breakthrough infections. Here, we report a remarkable genetic shift in a T/F virus from a participant of an acute HIV infection cohort_RV217 study. It resulted in substitution of histidine at position 173 to tyrosine (H173Y) at week 24 (wk 24) after infection, coinciding with the disappearance of strictly H173-specific first wave antibodies. Intriguingly, a second wave antibodies emerged against the escaped Y173 variant that displayed increased breadth recognizing both the H173 and Y173 epitopes. This differential antibody responses towards variant epitopes were recapitulated in a mouse model. Structural analyses suggest distinct conformations for H173 and Y173 variants which might have led to antibody responses with different reactivity and breadth. Given the occurrence of conformational dynamism in the V2 region, combinatorial V2 vaccine candidates consisting of numerous conformational variants in the natural HIV-1 diversity were designed and tested as an immunogen. These libraries, especially the Y173 variant libraries that also contained a V1 loop deletion showed increased breadth and cross-reactivity to diverse HIV-1 Env proteins. This combinatorial design might be a powerful strategy in the future design of highly efficacious HIV-1 vaccine candidates. Author summaryAfter numerous HIV-1 vaccine failures, only one human clinical study, RV144 has demonstrated protection with modest efficacy (31.2%) by virtue of antibody responses directed to V2-region of the Env that were correlated with reduced HIV acquisition. In natural infection, there occurs an evolutionary race between virus and the host immune system, as a result of which mutants of virus that escape the immune pressure are positively selected. Similarly, in vaccinated individuals, breakthrough infections occur when the infecting virus is able to escape from vaccine generated immune response compromising vaccine efficacy. Systematic learning of how these escape signatures are positively selected during the course of infection can have implications in designing a vaccine that can effectively counteract breakthrough infections. In the current study, we took an unprecedented approach of studying evolution of T/F viruses in acutely infected individuals to identify early V2-specific escape mutations and further study these mutations through biochemical, immunological and structural aspects. The knowledge obtained from these analyses was used to rationally design combinatorial vaccine libraries encompassing V2 variants mirroring natural HIV-1 population and assess their response in mice. The resultant vaccines generated antibodies were found to broadly cross-react diverse Env proteins. Such immune escape guided rationally designed vaccines have the potential to overcome breakthrough infections and improve vaccine efficacy. Striking image O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/448593v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@101ab9eorg.highwire.dtl.DTLVardef@aa367dorg.highwire.dtl.DTLVardef@df68aforg.highwire.dtl.DTLVardef@151c5ea_HPS_FORMAT_FIGEXP M_FIG C_FIG